The present invention relates, inter alia, to a bioactive product, an extrudable bioactive composition, a method for manufacturing a bioactive product and a method for delivering the bioactive contained in the product to a user. The bioactive agent may be, but is not limited to, a pharmaceutical.
The history of solid pharmaceutical dosage forms is straightforward. It began with bioactive powders and these evolved into pressed tablets. Pressed tablet led to capsules and caplets and eventually variants of these evolved which led to liquid core gels etc. Sustained release tablets, such as the osmotic pump system developed by Dr. Zaffaroni at Alza, followed and allowed for sustained release in the GI tract. The next advance was the orally dissolving tablet (ODT) which has been employed to ease dose administration for patients who have difficulty swallowing conventional tablets and capsules, as well as ODT based buccal delivery products such as Cephalon's Fentora®—an ODT system used to administer fentanyl buccally. Various novel methods of manufacturing such ODTs where taught, such as lyophilized quick dissolve forms (ZYDIS®), effervescent quick dissolve systems (CIMA) and ODTs based on a spun sugar matrix (invented by the present inventor, see e.g. U.S. Pat. No. 4,855,326). Copycat, inferior ODT products were then sold, largely based on using tableting processes at low dyne pressure, leading to proposed FDA rule codification to ensure that ODT products actually dissolve quickly (see FDA Draft Guidance dated April 2007 at http://www.fda.gov/CDER/guidance/5909dft.htm).
The next evolution was quick dissolve thin film (partly invented by the present inventor). Thin films are typically made using wet casting manufacturing process and were definitely film as they could only be up to a maximum of 10 mils thick, it being commonly understood that matrix like products become “sheets” when they exceed a thickness of 10 mils. Wet cast film manufacture and products are described in recently granted U.S. Pat. No. 7,425,292 invented by the present inventor: “The films may initially have a thickness of about 500 μm to about 1,500 μm, or about 20 mils to about 60 mils, and when dried have a thickness from about 3 μm to about 250 μm, or about 0.1 mils to about 10 mils. Desirably, the dried films will have a thickness of about 2 mils to about 8 mils, and more desirably, from about 3 mils to about 6 mils.” See also U.S. Pat. No. 5,948,430, disclosing wet cast thin film compositions, and stating that “the thickness of films should not exceed 2.7 mils so as to prevent adverse mouth feel.” The thickness of commercially available wet cast pharmaceutical film products was measured and found to range from 3 mils—GSK's Breath Right Snore Relief identified as made by MonoSol Rx; 4 mils—Fleet's Pedialax® senna product identified as made by MonoSol Rx, and 6 mils—Novartis' Triaminc® detromethorphan 7.5 mgs which is understood to be manufactured for Novartis by Adhesives Labs of Glen Rock, Pa.
Limitations on wet cast film thickness reflect in part the need to dry the highly aqueous film compositions which gave a practical limitation to the thickness of these films, as well as difficulties in achieving certain wet thicknesses in the coating process itself, discussed herein and related to the challenge of casting the higher molecular weight polymers associated with sufficient viscosity to achieve higher coating thicknesses. Water also serves to lower viscosity. The wet casting process cannot practically deal with very high viscosities as such viscosities cannot be reliably cast using known casting systems. Such limitations point to the utility of the new inventive steps that are shown in this application.
Thickness limitations associated with wet cast films tend to limit loading due to the lack of load carrying ability of the resulting dosage form. This was especially true if taste masking was needed (of course, many high value drug targets still fit within the loading capabilities of wet cast films). Thickness limitations also enable that films are fast dissolving. For example, MonoSol Rx states on its website that it “[specializes in] quick dissolving thin film pharmaceutical products” and further stated in its registration statement with the Securities and Exchange Commission on Form S-1 that “compared to quick-dissolve tablet technologies, our strips disintegrate faster.” Other companies with wet cast film making competencies, such as Adhesives Research, Lohmann Therapeutic Systems, Applied Pharmaceutical Research of Switzerland, Labtec of Germany, and Lavipharm of Greece describe their products and technologies in similar terms.
As noted above, edible films are typically made using a wet casting process. In discussing this art, applicant pointedly uses the term “sheet and not “film”. This is because the inherent properties of the wet casting manufacturing process—as currently understood—do not allow for the manufacture of thicker sheets (we also refer to “sheets” by a proprietary term “slabs”). Thickness can often relate to dissolution time especially if certain formulae are used. Wet cast edible films are typically quickly dissolving products, and practitioners have struggled—without success—to extend the disintegration time of wet cast edible thin film products where a slower dissolving product would be more appropriate for the intended use. One of the principle problems is that polymer molecular weight is frequently in a direct relationship to viscosity and wet casting is unable to deal with high viscosities.
The development of wet cast edible packaging films for various food and other applications commenced at least fifty years ago (see http://www.watson-inc.com/about_history.php). Other historical antecedents can be seen the wet cast manufacture of fruit pulps as well as rice based films in Asia.
Wet cast monolayer film compositions for pharmaceutical and vitamin delivery are disclosed in Fuchs et al. U.S. Pat. No. 4,136,162 issued Jan. 23, 1979. Schmidt discloses bilayer film compositions for pharmaceutical and food uses in U.S. Pat. No. 4,849,246 issued Jul. 18, 1989.
The inventor Horst Zerbe was issued U.S. Pat. No. 5,948,430 for film compositions for therapeutic agents and breath freshening agents. Zerbe notes, the thickness of films should not exceed 2.7 mils so as to prevent adverse mouth feel. The assignee of this patent, Lohmann Therapeutic Systems (“LTS”), is credited with the manufacture of the first edible film to enjoy commercial succeed—namely, the 2001 commercial launch of pullulan based Listerine PocketPaks® Breath Strips (a product described more fully in Leung et al. 6596298 “Fast dissolving orally consumable films” and Leung et al. 6923981).
The Listerine PocketPaks® film is a very rapidly dissolving film. It dissolves in fewer than ten seconds and has a weight of just 33 mg. The product contains high moisture content and uses water to help impart the product with flexibility (a trait easily demonstrated by drying a Listerine strip—at which point it becomes very brittle and will crack and break when bent).
From breath freshening, wet cast film technology has moved to over-the-counter pharmaceutical products. The emphasis has still been on achieving rapid disintegration in the mouth. Noted thin film drug delivery company MonoSol Rx LLC describes its film technology on its website thusly: “MonoSol Rx has developed a thin film drug delivery technology that is more stable, durable and quicker dissolving than other conventional dosage forms. The thin film, which is similar in size, shape and thickness to a postage stamp, has the ability to carry very low doses of prescription products that are highly uniform, to larger doses up to 80 mg. [italics added].” Those schooled in the art will understand that certain loading achievements are sui generis. The highest loading of a commercial thin film product for a “conventional” active ingredient is Bendadryl®'s 25 mg of diphenhydramine. Novartis also markets a 62.5 mg simethicone product under the Gas-X® brand but such loading is attributable to the unique characteristics of simethicone.
Other pharmaceutical thin film developers, such as LTS, Labtec, Adhesives Research, Lavipharm and Applied Pharma Research describe their film technologies in similar ways. It should be noted that these descriptions of the wet cast products do not address whether the active material is water soluble or insoluble and whether it requires taste masking or does not require taste masking. These factors can have a major effect on loading of the active ingredient as stated above.
The transition of thin film drug delivery into pharmaceutical products required a new focus on meeting pharmaceutical criteria, like achieving and maintaining content uniformity of drug during the wet cast manufacturing process. Wet cast compositional film art developed that could load increasing amounts of drug with continuing emphasis on quick disintegration of the film (see e.g. Yang et al. U.S. Pat. Nos. 7,357,891 and 7,425,292 both of which include the current inventor).
One limitation of wet cast technology is the difficulty—indeed, the inability to wet cast films beyond a certain thickness (or loading) range. This is due to the relationship between viscosity and coating thickness and drying, which creates a practical limitation on the ability to coat beyond certain thickness levels, and the difficulty removing moisture from films past a certain thickness levels, even if they are successfully cast.
Limitations on thickness translate into limits on the amount of bioactive ingredient a film can carry as well as whether absorption modifiers such as ion exchange resins can be carried. As noted above, the largest amount of solid active delivered by a commercially available film is 25 mg of diphenhydramine in Pfizer's fast dissolving Benadryl® strip. Likewise, limitations on thickness also limit the extension of dissolution time of the film matrix. The challenge of extending dissolution times in monolayer wet cast media is evident in Fankhauser et al US 2007/0202057 A1, a case directed at wet cast films containing the drug nicotine. This case uses bench scale formulation tricks including an ice water bath (to gel the polymer) to coax a monolayer wet cast film to a claimed fifteen minute disintegration time. That such a practice would involve immense challenges—arguably impossible—to scale to commercial manufacture is readily apparent.
Others have suggested the lamination of multiple cast films to slow the dissolution of the dosage form (see, e.g. LTS's website). This method is undoubtedly more practical from a manufacturing perspective than Fankhauser's proposed solution, but too costly to practice—particularly in the pharmaceutical space. Thus it is not surprising that such multiple film laminates are not yet seen in the marketplace as commercial products.
Even monolayer wet casting can be relatively expensive. Commercial equipment involves long drying ovens and is too heavy to be moved, requiring specialized and dedicated production suites. Drying requires substantial volumes of filtered air requiring specialized utilities, and substantial amounts of heat energy to remove moisture. With increasing energy costs this is of growing importance in aqueous cast film.
Two additional points must be made—namely, the physical strength and physical stability of wet cast films. Wet cast films are typically cast on a substrate or backing paper. Among other things, the substrate lends physical strength to the film in processing until the film is delaminated from the substrate. However additional costs and process steps to include the use of a substrate backing are involved. Also, the backing can be problematic in terms of the uniform distribution of the cast material on the substrate.
If such films lack the requisite pliability and tensile strength, they will tend to break during packaging causing substantial losses in process yield. Such breakage issues presumably led to the filing of a patent on methods of film splicing by Novartis (Slominski et al US 20060207721 A1). MonoSol Rx makes the most pliable, strong wet cast films, using their polyethylene oxide (PEO) based compositions (See Yang et al. US 2005/0037055 A1). The strength of these films has led to the subsequent use of PEO in formulations commercially sold by Novartis. The reality is that physical strength and resulting breakage and process yield issues have been significant problems for many of the non-PEO wet cast films.
Drying wet cast films requires exacting direction of the drying air in order to avoid surface skin formation and yet requires sufficient flow of hot air to dry off the water content. However, here too, in aqueous wet cast film, the air can be principally directed to the top or bottom of the drying film consistent with the flow patterns permitted in modern dryers (see U.S. Pat. No. 7,425,292).
The related issue of physical stability is also an issue for many wet cast films—expensive barrier packaging is often used as a matter of necessity. Still, physical stability is not always a given. Boots Chemists launched a Vitamin C strip manufactured by BioProgress in Tampa Fla. that had to be removed from the shelves because it was crumbling in the package—earning the name “chips not strips.” This story is not unique—many projects have failed to move out from development to commercialization due to physical stability issues.
In addition, the mixing of wet based compositions for casting itself raises certain challenges. First, the solvent itself adds volume to the mix. Wet compositions may tend to adhere to mixing vessels and any transit piping leading to yield losses. They can also involve complex fluidic issues in transit to the casting head.
Foaming may be in issue. Wet mixtures must be de-gassed to avoid air bubbles which can reduce content uniformity. Furthermore, cast aqueous film mixtures may tend to aerate when the aqueous mixture is formed through the mixing process. This then requires deaeration so as not to interfere with uniformity. The deaeration of cast film involves the pulling of vacuum over the wet mixture and the inclusion of various types of deaerators like simethicone etc. Simply put, in cast film, mixing may introduce air in the aqueous mix in cast film and vacuum and deaerating agents may be used to remove it and preserve uniformity. See, Fuisz et al. US 20080075825 A1. In our extruded, non aqueous film this hazard is not present.
Many of the above observations concerning aqueous wet casting apply equally to wet casting that employs non-water solvents.
Extruded edible products have a lengthy history—confections were being extruded in the 1920's (See P. B. Laskey U.S. Pat. No. 1,492,600). Extrusion has more recently been used in medical device manufacture and in the making of transdermal drug delivery systems—of course, these are both non-edible and insoluble. See, generally, Pharmaceutical Extrusion Technology, edited by Issac Ghebre-Sellassie and Charles Martin (2007), the content of which is incorporated herein in its entirety.
Inspired by the success of transdermal drug delivery systems, work began to extrude soluble, edible sheets and films for drug delivery use.
Schiraldi et al. (U.S. RE33,093) discloses bioadhesive monolayer extruded films, under 10 mils, composed of principally of polyethylene oxide together with a lesser amount of HPC, a water insoluble polymer; a plasticizer and a medicament. See also Mooney and Schiraldi, U.S. Pat. No. 6,072,100 disclosing compositions extruded films and sheets comprising a composition of PEO or HPC, a water polymer derived from a carboxylic aid, 30-80% plasticizer and up to 10% of a medicament.
Michael Repka and James McGinnity disclose hot melt extruded sheets with a thickness of 10-13 mils using a 50-50 ratio PEO and HPC, together with 3% of Vitamin E TPGS (see “Influence of Vitamin E TPGS on the properties of hydrophilic films produced by hot melt extrusion,” International Journal of Pharmaceutics 202 (2000) 63-70).
Repka et al U.S. Pat. No. 6,375,963 issued Apr. 23, 2002 disclose a hot-melt extruded film and method of preparation thereof. The inventors note that “[f]ilms comprising pure hydroxypropylcellulose (HPC) and other water-soluble or water-swellable polymers cannot be readily produced by hot-melt extrusion due to the high stress that is exhibited on the extruder. Therefore plasticizers have been added to the HPC and other polymers” and that “the prior art does not disclose that films comprising a major portion of HPC and other water-soluble or water-swellable polymers can be produced by hot-melt extrusion in the absence of a plasticizer.” To solve this problem Repka et al propose using a bioadhesive polymer instead of a plasticizer. The film of Repka et al is made from a precursor composition containing at least a water soluble or water swellable thermoplastic polymer, preferably HPC and/or PEO, and a bioadhesive polymer. The film can also contain a therapeutic agent, preservative, buffering agent, antioxidant, super-disintegrant or absorbent, flavorant, colorant, water insoluble polymer, organic acid, surfactant, film modifier, and/or cross-linking agent. The film does not contain a conventional plasticizer or a material which is generally recognized in the art as a plasticizer for extruded films. Repka et al claim, inter alia, a hot-melt extruded film including one or more water-soluble or water-swellable thermoplastic polymer or polymers, a therapeutic agent; and a bioadhesive polymer. The bioadhesive polymer is selected from the group consisting of polycarbophil, carbomer, one or more acrylic polymers, one or more polyacrylic acids, copolymers of these polymers, a water soluble salt of a co-polymer of methyl vinyl ether and maleic acid or anhydride, a combination thereof and their salts.
A review of the Orange Book indicates that none of the above extrusion patents are used in an FDA approved pharmaceutical product nor are any such patents referenced on any over-the-counter product.
As the art demonstrates, practitioners have struggled to achieve required flexibility in hot melt extruded pharmaceutical films, and have relied on PEO, polycarbophil or extreme levels of plasticizer to achieve such flexibility of the sheet or film. Neither PEO nor polycarbophil is approved for food use outside of the US. Additionally, PEO is a very expensive polymer that is ill suited from a cost perspective and may tend to dissolve too quickly for many applications. As a result, the pharmaceutical art on extruded films and sheets provides little guidance for the composition of the present invention.
As is seen the pharmaceutical art concerning hot melt extrusion of sheets and/or films containing active ingredients involves real challenges which must be overcome, as they are by the present invention.
Thus, it is still desirable to provide a more efficient way to produce a bioactive containing sheet so as to allow the absorption of the bioactive agent. This is accomplished using a slab or sheet dosage form as put forth below.